Chronic fatigue syndrome (CFS) is a disease which has been present in human populations for a very long time. However, only recently have we begun to investigate its clinical and laboratory diagnostic features. At present, while there is a reasonably well-defined set of clinical signs characteristic of CFS, a collection of virological or immunological values remains to be established which can be used to make a firm laboratory diagnosis. In addition, we presently have no clear mechanism for the cause of CFS, either for its initiation or for the basis of its chronic nature. We propose to examine prospectively a cohort of CFS patients, diagnosed on clinical as well as on laboratory criteria, in conjunction with three sets of appropriate control populations. At present, evidence exists for the association of several viruses with CFS, although none of the data are as yet compelling. Our experiments therefore will be on a reasonably broad basis, involving a number of virological assays, in which we will use state-of-the-art technology to identify patterns of virus association in the CFS population, or in subsets of it. We will assay for HHV-6, human enterovirus, EBV antibodies and a human retrovirus (HTLV-II-like) in CFS and control tissues; a main thrust of the proposal will be the continuous correlation of the virological data with immunological and clinical data generated in other sections of this center grant. The working hypothesis is that an initiating factor (organic or functional) triggers immune imbalance, which allows virus infection or reactivation, which triggers further immune imbalance, and a chronic cycle is thus set up. In the last section of the proposal, we will investigate an in vitro model system (HHV-6 and EBV in lymphocytes) in which investigation of relationships between virus infection and cytokines can be assessed, with potential relevance for CFS in vivo. On the basis of these data, we expect to identify a set of criteria which will define the characteristics of CFS and will allow us to set more rigorous laboratory diagnostic criteria for the disease.